EP3416970A1 - Cortistatin analogs - Google Patents
Cortistatin analogsInfo
- Publication number
- EP3416970A1 EP3416970A1 EP16890889.5A EP16890889A EP3416970A1 EP 3416970 A1 EP3416970 A1 EP 3416970A1 EP 16890889 A EP16890889 A EP 16890889A EP 3416970 A1 EP3416970 A1 EP 3416970A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- cancer
- pharmaceutically acceptable
- disorder
- administration
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/08—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/26—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against hormones ; against hormone releasing or inhibiting factors
Definitions
- the present invention provides Cortistain analogs with pharmacological properties amendable to in vivo administration in humans for the treatment of disorders mediated by CDK8 and/or CDK19.
- HUVECs human umbilical vein endothelial cells
- Cortistatin A is currently the most selective member of the naturally occurring cortistatin family for cyclin-dependent kinase 8 (CDK8) and cyclin-dependent kinase 19 (CDK19), two kinases that coactivate the Mediator complex that is involved in the regulation of many RNA polymerase II-dependent genes. It has been shown using Cortistatin A that by inhibiting CDK8 and CDK19 acute myeloid leukemia (AML) growth can be abated.
- Patent 8,642,766 titled “Synthesis of (+) Cortistatin A and Related Compounds” along with 3-substituted amino derivatives in the A ring.
- the application of cortistatins for inhibition of retroviral replication is described in WO 2012/096934 titled “Inhibitors of Retroviral Replication”.
- Cortistatin A and analogs of Cortistatin A include have been described in: Chiu et al., Chemistry (2015), 21 : 14287-14291, titled “Formal Total Synthesis of (+)-Cortistatins A and J”; Valente et al., Current HIV Research (2015), 13 : 64- 79, titled "Didehydro-Cortistatin A Inhibits HIV-1 Tat Mediated Neuroinflammation and Prevents Potentiation of Cocaine Reward in Tat Transgenic Mice”; Motomasa et al., Chemical & Pharma.
- CDK8 is upregulated and amplified in a subset of human colon tumors and is known to transform immortalized cells and is required for colon cancer proliferation in vitro. Similarly, CDK8 has also been found to be overexpressed and essential for proliferation in melanoma. Kapoor, A. et al., Nature 468, 1105-1109 (2010). CDK8 has been shown to regulate several signaling pathways that are key regulators of both ES pluripotency and cancer.
- CDK8 activates the Wnt pathway by promoting expression of ⁇ -Catenin target genes (Firestein, R. et al., Nature 455, 547-551 (2008)) or by inhibiting E2F1, a potent inhibitor of ⁇ -Catenin transcriptional activity. Morris, E. J. et al., Nature 455, 552-556 (2008). CDK8 promotes Notch target gene expression by phosphorylating the Notch intracellular domain, activating Notch enhancer complexes at target genes. Fryer C. J. et al., Mol Cell 16:509-20 (2004).
- hERG is a protein which is part of the potassium ion channel, which contributes to the electrical activity of the heart that coordinates the heart's beating activity. When the electrical activity is compromised, it can result in a dangerous condition referred to as long QT prolongation.
- Compound A It has been discovered that Compound A is highly unusual among Cortistatin A analogs because it exhibits a combination of low hERG activity (wherein low hERG activity is defined as IC50 > 1 ⁇ ), high selectivity against off-target enzymes and receptors and low toxicity (no significant weight loss, for example, ⁇ 15% weight loss over 7 day dosing). The low toxicity results in higher tolerability of the drug, which allows for dosing at a higher level and thus better efficacy.
- CDK8 and/or CDK19 Given the therapeutic importance of inhibiting CDK8 and/or CDK19 in the treatment of tumors, cancer and other disorders mediated by these enzymes, it is a goal of the invention to identify compounds that selectively inhibit CDK8 and/or CDK19 and have advantageous medicinal properties.
- the present invention provides cortistatin derivatives of with advantageous properties for in vivo administration to a host, including a human, in need thereof.
- these novel derivatives have advantageous pharmacokinetics, low toxicity and/or other pharmacological properties which make them stand out among the class of cortistatins as superior candidates for human ministration.
- n 0, 1, 2, 3, or
- R 1 is selected from:
- R 2 is independently selected at each instance from: -OH, -OR 6 , alkyl, and haloalkyl;
- R 3 is alkyl;
- R 4 is independently selected at each instance from: -OH, -OR 6 , alkyl, and haloalkyl;
- R 5 is selected from: -(CH 2 )(y)C(0) R 7 R 8 , -(CR 7 2 )(y)C(0)R 8 , -(CH 2 ) (y) R 7 R 8 , - (CH 2 )(y)C(0)R 7 , -alkyl-C(0) R 7 R 8 , -alkyl- R 7 R 8 , and -alkyl-C(0)R 7 , wherein y is 1, 2, or 3;
- R 6 is selected from: hydrogen, -C(0)R 7 , alkyl, and haloalkyl;
- R 7 and R 8 are independently selected from: hydrogen, alkyl, alkenyl, and alkynyl.
- two R 2 substituents can combine to form a fused carbocycle.
- two R 2 substituents can combine to form an epoxide.
- two R 4 substituents can combine to form a fused carbocycle. In another embodiment, two R 4 substituents can combine to form an epoxide.
- CDK19 including a tumor, cancer, disorder related to abnormal proliferation, inflammatory disorder, immune disorder, or autoimmune disorder is provided that includes administering to a host in need thereof an effective amount of a compound of Formula 1, or its pharmaceutically acceptable salt, N-oxide, deuterated derivative, prodrug, and/or a pharmaceutically acceptable composition thereof optionally in a pharmaceutically acceptable carrier.
- One aspect of the present invention provides Compound B, Compound C, and Compound D, shown below.
- Each compound has a unique substituent at the 3-position of the A-ring.
- Compound B has a 2-hydroxyacetamide
- Compound C has an azetidine-3,3-diyldimethanol
- Compound D has a (3R,4S)-pyrrolidine-3,4-diol.
- a method for the treatment of a disorder mediated by CDK8 and/or CDK19 including a tumor, cancer, disorder related to abnormal proliferation, inflammatory disorder, immune disorder, or autoimmune disorder is provided that includes administering to a host in need thereof an effective amount of Compound B, C, or D or its pharmaceutically acceptable salt, N-oxide, deuterated derivative, prodrug, and/or a pharmaceutically acceptable composition thereof optionally in a pharmaceutically acceptable carrier.
- a deuterated derivative of a compound of Formula 1 is provided.
- Deuterium can replace one or more hydrogens in the compound.
- deuterium is substituted for hydrogen in one or more positions in the substituent on the 3-position of the A ring.
- deuterium is substituted for hydrogen in one or more positions in the A ring.
- deuterium is substituted for hydrogen in one or more positions in the B ring.
- deuterium is substituted for hydrogen in one or more positions in the C ring.
- deuterium is substituted for hydrogen in the methyl group at the bridge carbon between the C and D rings.
- deuterium is substituted for hydrogen in one or more positions in the D ring.
- deuterium is substituted for hydrogen in one or more positions in the isoquinoline ring.
- a deuterated derivative of Compound B, Compound C, or Compound D is provided.
- Deuterium can replace one or more hydrogens in the compound.
- the alpha hydrogens in the hydroxyacetamide can be replaced with deuterium.
- a hydrogen in the azetidine can be replaced with deuterium.
- a hydrogen in (3R, S)-pyrrolidine-3,4-diol can be replaced with deuterium.
- the active compound or its pharmaceutically acceptable salt, N-oxide, deuterated derivative, prodrug, and/or a pharmaceutically acceptable composition thereof as disclosed herein is also useful for administration in combination or alternation with one or more additional pharmaceutical agents for use in combination therapy, as described in more detail herein.
- the present invention thus includes at least the following features:
- a compound of Formula 1 for use in treating a medical disorder which is associated with CDK8 and/or CDK19, such as a tumor, cancer, abnormal cellular proliferation, an inflammatory disorder, an immune disorder, or an autoimmune disorder;
- Compounds B, C, and D or a pharmaceutically acceptable salt, N-oxide, deuterated derivative, prodrug, and/or a pharmaceutically acceptable composition thereof, for use in treating a medical disorder which is associated with CDK8 and/or CDK19, such as a tumor, cancer, abnormal cellular proliferation, an inflammatory disorder, an immune disorder, or an autoimmune disorder;
- Figure 1 is a dose-response curve of MOLM-14 growth on day 10 when exposed to various concentrations of Compound D.
- the x-axis is concentration of Compound D measured in nM and the y-axis is MOLM-14 growth measured as a percent.
- the present invention includes compounds with at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched.
- Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons.
- isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine such as 2 H, 3 H, U C, 13 C, 14 C, 15 N, 18 F 31 P, 32 P, 35 S, 36 CI, and 125 I respectively.
- isotopically labelled compounds can be used in metabolic studies (with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
- PET positron emission tomography
- SPECT single-photon emission computed tomography
- an 18 F labeled compound may be particularly desirable for PET or SPECT studies.
- Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
- isotopes of hydrogen for example, deuterium ( 2 H) and tritium ( 3 H) may be used anywhere in described structures that achieves the desired result.
- isotopes of carbon e.g., 13 C and 14 C, may be used.
- the isotopic substitution is deuterium for hydrogen at one or more locations on the molecule to improve the performance of the drug, for example, the pharmacodynamics, pharmacokinetics, biodistribution, half-life, stability, AUC, Tmax, Cmax, etc.
- the deuterium can be bound to carbon in a location of bond breakage during metabolism (an a- deuterium kinetic isotope effect) or next to or near the site of bond breakage (a ⁇ -deuterium kinetic isotope effect).
- Isotopic substitutions for example deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium.
- the isotope is 90%, 95% or 99% or more enriched in an isotope at any location of interest.
- deuterium is 90%, 95% or 99% enriched at a desired location. Unless otherwise stated, the enrichment at any point is above natural abundance and enough to alter a detectable property of the drug in a human.
- the compound of the present invention may form a solvate with solvents (including water). Therefore, in one embodiment, the invention includes a solvated form of the active compound.
- solvate refers to a molecular complex of a compound of the present invention (including a salt thereof) with one or more solvent molecules.
- solvents are water, ethanol, dimethyl sulfoxide, acetone and other common organic solvents.
- hydrate refers to a molecular complex comprising a compound of the invention and water.
- Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent may be isotopically substituted, e.g. D2O, d 6 -acetone, d 6 -DMSO.
- a solvate can be in a liquid or solid form.
- a stable active compound refers to a compound that can be isolated and can be formulated into a dosage form with a shelf life of at least one month.
- a stable manufacturing intermediate or precursor to an active compound is stable if it does not degrade within the period needed for reaction or other use.
- a stable moiety or substituent group is one that does not degrade, react or fall apart within the period necessary for use.
- Non-limiting examples of unstable moieties are those that combine heteroatoms in an unstable arrangement, as typically known and identifiable to those of skill in the art.
- a “dosage form” means a unit of administration of an active agent.
- dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, buccal, sublingual, topical, gel, mucosal, and the like.
- a “dosage form” can also include an implant, for example an optical implant.
- “Pharmaceutical compositions” are compositions comprising at least one active agent, and at least one other substance, such as a carrier. “Pharmaceutical combinations” are combinations of at least two active agents which may be combined in a single dosage form or provided together in separate dosage forms with instructions that the active agents are to be used together to treat any disorder described herein.
- a “pharmaceutically acceptable salt” is a derivative of the disclosed compound in which the parent compound is modified by making inorganic and organic, non-toxic, acid or base addition salts thereof.
- such salts can be prepared by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
- non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, where practicable.
- Salts of the present compounds further include solvates of the compounds and of the compound salts.
- the pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
- conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2)n
- carrier applied to pharmaceutical compositions/combinations of the invention refers to a diluent, excipient, or vehicle with which an active compound is provided.
- a "pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition/combination that is generally safe, non-toxic and neither biologically nor otherwise inappropriate for administration to a host, typically a human. In one embodiment, an excipient is used that is acceptable for veterinary use.
- a “patient” or “host” or “subject” is a human or non-human animal in need of treatment or prevention of any of the disorders as specifically described herein, including but not limited to by modulation of CDK8 and/or CDK19.
- the host is a human.
- a “patient” or “host” or “subject” also refers to for example, a mammal, primate (e.g., human), cows, sheep, goat, horse, dog, cat, rabbit, rat, mice, fish, bird, chicken, and the like.
- a “prodrug” as used herein, means a compound which when administered to a host in vivo is converted into a parent drug.
- the term “parent drug” means any of the presently described chemical compounds described herein.
- Prodrugs can be used to achieve any desired effect, including to enhance properties of the parent drug or to improve the pharmaceutic or pharmacokinetic properties of the parent.
- Prodrug strategies exist which provide choices in modulating the conditions for in vivo generation of the parent drug, all of which are deemed included herein.
- Non-limiting examples of prodrug strategies include covalent attachment of removable groups, or removable portions of groups, for example, but not limited to acylation, phosphorylation, phosphonylation, phosphoramidate derivatives, amidation, reduction, oxidation, esterification, alkylation, other carboxy derivatives, sulfoxy or sulfone derivatives, carbonylation or anhydride, among others.
- a “therapeutically effective amount” of a pharmaceutical composition/combination of this invention means an amount effective, when administered to a host, to provide a therapeutic benefit such as an amelioration of symptoms or reduction or diminution of the disease itself.
- a therapeutically effective amount is an amount sufficient to prevent a significant increase or will significantly reduce the detectable level of cancer in the patient's blood, serum, or tissues.
- Alkyl is a branched or straight chain saturated aliphatic hydrocarbon group. In one non- limiting embodiment, the alkyl group contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms. In one non-limiting embodiment, the alkyl contains from 1 to about 8 carbon atoms.
- the specified ranges as used herein indicate an alkyl group having each member of the range described as an independent species. In one embodiment the alkyl is 1 carbon long, 2 carbons long, 3 carbons long, 4 carbons long, 5 carbons long, 6 carbons long, 7 carbons long, 8 carbons long, 9 carbons long, or 10 carbons long.
- alkyl indicates a straight or branched alkyl group.
- alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane.
- the alkyl group is optionally substituted.
- Alkenyl is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds that may occur at a stable point along the chain.
- the specified ranges as used herein indicate an alkenyl group having each member of the range described as an independent species, as described above for the alkyl moiety.
- alkenyl include, but are not limited to, ethenyl and propenyl. In an alternative embodiment, the alkenyl group is optionally substituted.
- alkynyl examples include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.
- the alkynyl group is optionally substituted.
- Alkoxy is an alkyl group as defined above covalently bound through an oxygen bridge (- 0-).
- alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n- hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.
- an "alkylthio" or a "thioalkyl” group is an alkyl group as defined above with the indicated number of carbon atoms covalently bound through a sulfur bridge (-S-).
- the alkoxy group is optionally substituted as described above.
- the thioalkyl group is optionally substituted.
- Arylalkyl is an aryl group as defined herein attached through an alkyl group.
- Amino is -NH 2 .
- carbocyclyl is a saturated or partially unsaturated (i.e., not aromatic) group containing all carbon ring atoms and from 3 to 14 ring carbon atoms and zero heteroatoms in the non-aromatic ring system.
- a carbocyclyl group has 3 to 10 ring carbon atoms.
- a carbocyclyl group has 3 to 9 ring carbon atoms.
- a carbocyclyl group has 3 to 8 ring carbon atoms.
- a carbocyclyl group has 3 to 7 ring carbon atoms.
- a carbocyclyl group has 3 to 6 ring carbon atoms. In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms. In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms. In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms.
- Exemplary carbocyclyl groups include, without limitation, cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like.
- the carbocyclyl group can be saturated or can contain one or more carbon-carbon double or triple bonds.
- Carbocyclyl also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more heterocyclyl, aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
- each instance of carbocycle is optionally substituted with one or more substituents.
- the carbocyclyl group is an unsubstituted carbocyclyl.
- the carbocyclyl group is a substituted carbocyclyl.
- Haloalkoxy indicates a haloalkyl group as defined herein attached through an oxygen bridge (oxygen of an alcohol radical).
- Halo or "halogen” indicates independently any of fluoro, chloro, bromo or iodo.
- aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system.
- an aryl group has 6 ring carbon atoms (e.g., phenyl).
- an aryl group has 10 ring carbon atoms (e.g., naphthyl such as 1-naphthyl and 2-naphthyl).
- an aryl group has 14 ring carbon atoms (e.g., anthracyl).
- Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
- the present invention includes compounds of Formula 1 :
- n 0, 1, 2, or 3;
- n 0, 1, 2, 3, or 4;
- R 1 is selected from:
- R 2 is independently selected at each instance from: -OH, -OR 6 , alkyl, and haloalkyl;
- R 3 is alkyl;
- R 4 is independently selected at each instance from: -OH, -OR 6 , alkyl, and haloalkyl;
- R 5 is selected from: -(CH 2 )(y)C(0) R 7 R 8 , -(CR 7 2 )(y)C(0)R 8 , -(CH 2 ) (y) R 7 R 8 , - (CH 2 )(y)C(0)R 7 , -alkyl-C(0) R 7 R 8 , -alkyl- R 7 R 8 , and -alkyl-C(0)R 7 , wherein y is 1, 2, or 3;
- R 6 is selected from: hydrogen, -C(0)R 7 , alkyl, and haloalkyl;
- R 7 and R 8 are independently selected from: hydrogen, alkyl, alkenyl, and alkynyl.
- two R 2 substituents can combine to form a fused carbocycle.
- two R 2 substituents can combine to form an epoxide.
- two R 4 substituents can combine to form a fused carbocycle. In another embodiment, two R 4 substituents can combine to form an epoxide.
- the present invention also includes Compound B, Compound C, and Compound D or a pharmaceutically acceptable salt, N-oxide, deuterated derivative, prodrug, and/or a pharmaceutically acceptable composition thereof:
- the present invention provides pharmaceutical compositions comprising a compound of the present invention or a pharmaceutically acceptable composition, salt, isotopic analog such as a deuterated derivative, or prodrug thereof, and a pharmaceutically acceptable excipient.
- the compound is present in an effective amount, e.g., a therapeutically effective amount or a prophylactically effective amount.
- compositions agents include solvents, diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
- General considerations in the formulation and/or manufacture of pharmaceutical compositions agents can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21 st Edition (Lippincott Williams & Wilkins, 2005).
- compositions described herein can be prepared by any method known in the art of pharmacology.
- preparatory methods include the steps of bringing a compound of the present invention or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof (the "active ingredient") into association with the excipient and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping and/or packaging the product into a desired single- or multi-dose unit.
- compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
- a "unit dose" is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
- the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.
- Relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and/or any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered.
- the composition may comprise between 0.1% and 100% (w/w) active ingredient.
- compositions used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
- Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, etc., and combinations thereof.
- Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, etc., and combinations thereof.
- cross-linked poly(vinyl-pyrrolidone) crospovidone
- sodium carboxymethyl starch sodium starch glycolate
- Exemplary surface active agents and/or emulsifiers include natural emulsifiers ⁇ e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays ⁇ e.g. bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g.
- natural emulsifiers ⁇ e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin
- colloidal clays ⁇ e.g. bentonite [aluminum silicate] and Vee
- stearyl alcohol cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g.
- polyoxyethylene monostearate [Myrj 45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor), polyoxyethylene ethers, (e.g.
- polyoxyethylene lauryl ether [Brij 30]), poly(vinyl-pyrrolidone), di ethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and/or combinations thereof.
- Exemplary binding agents include starch (e.g. cornstarch and starch paste), gelatin, sugars (e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g.
- acacia sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxy ethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, etc., and/or combinations thereof.
- Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
- antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabi sulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabi sulfite, and sodium sulfite.
- Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.
- EDTA ethylenediaminetetraacetic acid
- salts and hydrates thereof e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like
- citric acid and salts and hydrates thereof e.g., citric acid mono
- antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
- antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
- Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
- Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
- preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabi sulfite, potassium sulfite, potassium metabi sulfite, Glydant Plus, Phenonip, methylparaben, Germall 1 15, Germaben II, Neolone, Kathon, and Euxyl.
- the preservative is an anti-oxidant.
- the preservative is a chelating agent.
- Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer
- Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, etc., and combinations thereof.
- Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckt
- Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof.
- Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
- the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils ⁇ e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
- inert diluents commonly used in the art such as, for example, water or other solvents,
- the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
- adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
- the conjugates of the invention are mixed with solubilizing agents such as Cremophor, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, polymer conjugates (e.g., IT- 101/CLRXlOl), and combinations thereof.
- sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation can be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
- acceptable vehicles and solvents that can be employed are water, Ringer's solution, U. S.P. and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil can be employed including synthetic mono- or diglycerides.
- fatty acids such as oleic acid are used in the preparation of injectables.
- the injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
- the absorption of the active ingredient In order to prolong the effect of the active ingredient, it is often desirable to slow the absorption of the active ingredient from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the active ingredient then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered form is accomplished by dissolving or suspending the active ingredient in an oil vehicle.
- compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
- suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
- Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
- the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol mono
- Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
- the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
- Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
- the active ingredient(s) can be in micro-encapsulated form with one or more excipients as noted above.
- the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
- the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose or starch.
- Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
- the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
- opacifying agents include polymeric substances and waxes.
- Dosage forms for topical and/or transdermal administration of a compound of this invention may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and/or patches.
- the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier and/or any needed preservatives and/or buffers as can be required.
- the present invention contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body.
- Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium.
- the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.
- Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices such as those described in U.S. Patents 4,886,499; 5,190,521; 5,328,483; 5,527,288; 4,270,537; 5,015,235; 5, 141,496; and 5,417,662.
- Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin, such as those described in PCT publication WO 99/34850 and functional equivalents thereof.
- Jet injection devices which deliver liquid vaccines to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable.
- Jet injection devices are described, for example, in U.S. Patents 5,480,381; 5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569, 189; 5,704,911; 5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335; 5,503,627; 5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880; 4,940,460; and PCT publications WO 97/37705 and WO 97/13537.
- Ballistic powder/particle delivery devices which use compressed gas to accelerate vaccine in powder form through the outer layers of the skin to the dermis are suitable.
- conventional syringes can be used in the classical mantoux method of intradermal administration.
- Formulations suitable for topical administration include, but are not limited to, liquid and/or semi liquid preparations such as liniments, lotions, oil in water and/or water in oil emulsions such as creams, ointments and/or pastes, and/or solutions and/or suspensions.
- Topically- administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent.
- Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
- a pharmaceutical composition can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity.
- a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers or from about 1 to about 6 nanometers.
- Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self-propelling solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container.
- Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers.
- Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.
- Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure.
- the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition.
- the propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).
- compositions formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension.
- Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device.
- Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate.
- the droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.
- formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition of the invention.
- Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered, by rapid inhalation through the nasal passage from a container of the powder held close to the nares.
- Formulations for nasal administration may, for example, comprise from about as little as
- a pharmaceutical composition of the invention can be prepared, packaged, and/or sold in a formulation for buccal administration.
- Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein.
- formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient.
- Such powdered, aerosolized, and/or aerosolized formulations, when dispersed may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.
- a pharmaceutical composition can be prepared, packaged, and/or sold in a formulation for ophthalmic administration.
- Such formulations may, for example, be in the form of eye drops including, for example, a 0.1/1.0%) (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier.
- Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein.
- Other ophthalmically administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are contemplated as being within the scope of this invention.
- compositions are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to non-human animals. Modification of pharmaceutical compositions suitable for administration to humans to render the compositions suitable for administration to animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation. General considerations in the formulation and/or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21 st ed., Lippincott Williams & Wilkins, 2005.
- compositions and/or kits may comprise a provided composition and a container (e.g., a vial, ampoule, bottle, syringe, and/or dispenser package, or other suitable container).
- a container e.g., a vial, ampoule, bottle, syringe, and/or dispenser package, or other suitable container.
- provided kits may optionally further include a second container comprising a suitable aqueous carrier for dilution or suspension of the provided composition for preparation of administration to a subject.
- contents of provided formulation container and solvent container combine to form at least one unit dosage form.
- a single container may comprise one or more compartments for containing a provided composition, and/or appropriate aqueous carrier for suspension or dilution.
- a single container can be appropriate for modification such that the container may receive a physical modification so as to allow combination of compartments and/or components of individual compartments.
- a foil or plastic bag may comprise two or more compartments separated by a perforated seal which can be broken so as to allow combination of contents of two individual compartments once the signal to break the seal is generated.
- a pharmaceutical pack or kit may thus comprise such multi-compartment containers including a provided composition and appropriate solvent and/or appropriate aqueous carrier for suspension.
- instructions for use are additionally provided in such kits of the invention.
- Such instructions may provide, generally, for example, instructions for dosage and administration.
- instructions may further provide additional detail relating to specialized instructions for particular containers and/or systems for administration.
- instructions may provide specialized instructions for use in conjunction and/or in combination with additional therapy.
- a method of treating a disorder mediated by CDK8 and/or CDK19 kinase activity in a host, including a human comprising administering an effective amount of a compound or its pharmaceutically acceptable salt, N-oxide, deuterated derivative, prodrug, and/or a pharmaceutically acceptable composition thereof as described herein optionally in a pharmaceutically acceptable carrier.
- disorders mediated by CDK8 and CDK19 include tumors, cancers, disorders related to abnormal cellular proliferation, inflammatory disorders, immune disorders, and autoimmune disorders.
- a method of treating a disorder that is not mediated by CDK8 and/or CDK19 kinase activity in a host, but is nonetheless mediated by one or more of the compounds described herein or their pharmaceutically acceptable salts, including a human comprising administering an effective amount of a compound or its pharmaceutically acceptable salt, N-oxide, deuterated derivative, prodrug, and/or a pharmaceutically acceptable composition thereof, as described herein optionally in a pharmaceutically acceptable carrier.
- the method is an in vitro method. In certain embodiments, the method is an in vivo method. In another aspect, a method of treating a condition associated with CDK8 and/or CDK19 kinase activity is provided, comprising administering to a subject in need thereof a compound of the present invention or a pharmaceutically acceptable composition, salt, isotopic analog such as a deuterated derivative, or prodrug thereof.
- condition associated with CDK8 and/or CDK19 kinase activity is a disorder related to abnormal cellular proliferation.
- Abnormal cellular proliferation notably hyperproliferation
- Psoriasis is a benign disease of human skin generally characterized by plaques covered by thickened scales. The disease is caused by increased proliferation of epidermal cells of unknown cause. Chronic eczema is also associated with significant hyperproliferation of the epidermis.
- Other diseases caused by hyperproliferation of skin cells include atopic dermatitis, lichen planus, warts, pemphigus vulgaris, actinic keratosis, basal cell carcinoma and squamous cell carcinoma.
- hyperproliferative cell disorders include blood vessel proliferation disorders, fibrotic disorders, autoimmune disorders, graft-versus-host rejection, tumors and cancers.
- Blood vessel proliferative disorders include angiogenic and vasculogenic disorders. Proliferation of smooth muscle cells in the course of development of plaques in vascular tissue cause, for example, restenosis, retinopathies and atherosclerosis. Both cell migration and cell proliferation play a role in the formation of atherosclerotic lesions.
- Fibrotic disorders are often due to the abnormal formation of an extracellular matrix.
- fibrotic disorders include hepatic cirrhosis and mesangial proliferative cell disorders.
- Hepatic cirrhosis is characterized by the increase in extracellular matrix constituents resulting in the formation of a hepatic scar.
- Hepatic cirrhosis can cause diseases such as cirrhosis of the liver.
- An increased extracellular matrix resulting in a hepatic scar can also be caused by viral infection such as hepatitis. Lipocytes appear to play a major role in hepatic cirrhosis.
- Mesangial disorders are brought about by abnormal proliferation of mesangial cells.
- Mesangial hyperproliferative cell disorders include various human renal diseases, such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, transplant rejection, and glomerulopathies.
- Rheumatoid arthritis is generally considered an autoimmune disease that is thought to be associated with activity of autoreactive T cells, and to be caused by autoantibodies produced against collagen and IgE.
- pulmonary embolism Other disorders that can include an abnormal cellular proliferative component include Bechet's syndrome, acute respiratory distress syndrome (ARDS), ischemic heart disease, post- dialysis syndrome, leukemia, acquired immune deficiency syndrome, vasculitis, lipid histiocytosis, septic shock and inflammation in general.
- ARDS acute respiratory distress syndrome
- ischemic heart disease post- dialysis syndrome
- leukemia CAD
- acquired immune deficiency syndrome vasculitis
- vasculitis lipid histiocytosis
- septic shock inflammation in general.
- condition associated with CDK8 and/or CDK19 kinase activity is a diabetic condition.
- condition associated with CDK8 and/or CDK19 kinase activity is a viral disease.
- CDK8 activity plays a role in interferon response, which is also important in cancer cell survival.
- Treatment with Cortistatin A increases expression of genes in MOLM-14 AML cells that have been identified as interferon gamma signaling genes and interferon responsive genes. Viruses such as HIV block interferon induction to allow more effective replication. Further, Cortistatin A has been shown to inhibit the HIV virus as well as the HIV viral protein TAT-1.
- the condition associated with CDK8 and/or CDK19 kinase activity is an infection.
- the infection is a bacterial infection.
- the infection is a fungal infection.
- the infection is a protozoal infection.
- the infection is a viral infection.
- the viral infection is a retroviral infection, and the virus is a retrovirus, i.e., of the family Retroviridae .
- the viral infection is a retroviral infection, and the virus is of the family Retroviridae and subfamily Orthoretrovirinae, Alpharetrovirus, Betaretrovims, Deltaretrovirus, Epsilonretrovims, Gammaretrovims, or Lentivirus.
- the viral infection is a retroviral infection, and the virus is of the family Retroviridae and subfamily Lentivirus.
- virus of the subfamily Lentivirus include human immunodeficiency virus (HIV), simian immunodeficiency virus (SIV), feline immunodeficiency virus (FIV), equine infectious anemia virus (EIAV), and Visna virus are all examples of lentiviruses.
- the viral infection is a human immunodeficiency virus (HIV) infection.
- Other viral infections contemplated are infections with the herpes simplex virus (HSV), human immunodeficiency virus (HIV) or human cytomegalovirus (HCMV).
- the virus is an oncovirus, i.e., a virus which is associated with oncogenesis and/or causes cancer.
- treatment of the viral infection is associated with inhibition of CDK8 and/or CDK19 kinase activity.
- a compound of the present invention and its pharmaceutically acceptable derivatives or salts or pharmaceutically acceptable formulations containing these compounds are useful in the prevention and treatment of HIV infections and other related conditions such as AIDS-related complex (ARC), persistent generalized lymphadenopathy (PGL), AIDS-related neurological conditions, anti-HIV antibody positive and HIV-positive conditions, Kaposi's sarcoma, thrombocytopenia purpura and opportunistic infections.
- these compounds or formulations can be used prophylactically to prevent or retard the progression of clinical illness in individuals who are anti-HIV antibody or HIV-antigen positive or who have been exposed to HIV.
- a compound of the present invention and its pharmaceutically acceptable derivatives or pharmaceutically acceptable formulations containing these compounds are also useful in the prevention and treatment of HBV infections and other related conditions such as anti-HBV antibody positive and HBV-positive conditions, chronic liver inflammation caused by HBV, cirrhosis, acute hepatitis, fulminant hepatitis, chronic persistent hepatitis, and fatigue.
- HBV infections and other related conditions such as anti-HBV antibody positive and HBV-positive conditions, chronic liver inflammation caused by HBV, cirrhosis, acute hepatitis, fulminant hepatitis, chronic persistent hepatitis, and fatigue.
- These compounds or formulations can also be used prophylactically to prevent or retard the progression of clinical illness in individuals who are anti-HBV antibody or HBV-antigen positive or who have been exposed to HBV.
- the condition is associated with an immune response.
- Cutaneous contact hypersensitivity and asthma are just two examples of immune responses that can be associated with significant morbidity.
- Others include atopic dermatitis, eczema, Sjogren's Syndrome, including keratoconjunctivitis sicca secondary to Sjogren's Syndrome, alopecia areata, allergic responses due to arthropod bite reactions, Crohn's disease, aphthous ulcer, ulceris, conjunctivitis, keratoconjunctivitis, ulcerative colitis, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions.
- immunologically mediated leukocyte infiltration In atopic dermatitis, and eczema in general, immunologically mediated leukocyte infiltration (particularly infiltration of mononuclear cells, lymphocytes, neutrophils, and eosinophils) into the skin importantly contributes to the pathogenesis of these diseases. Chronic eczema also is associated with significant hyperproliferation of the epidermis. Immunologically mediated leukocyte infiltration also occurs at sites other than the skin, such as in the airways in asthma and in the tear producing gland of the eye in keratoconjunctivitis sicca.
- novel method may also be useful in reducing the infiltration of skin by malignant leukocytes in diseases such as mycosis fungoides.
- These compounds can also be used to treat an aqueous-deficient dry eye state (such as immune mediated keratoconjunctivitis) in a patient suffering therefrom, by administering the compound topically to the eye.
- condition associated with CDK8 and/or CDK19 kinase activity is a degenerative disorder, e.g., Alzheimer's disease (AD) or Parkinson's Disease.
- AD Alzheimer's disease
- Parkinson's Disease a degenerative disorder
- a method of treating a ⁇ -catenin pathway-associated condition comprising administering to a subject in need thereof a compound of the present invention or a pharmaceutically acceptable composition, salt, isotopic analog (such as a deuterated derivative), or prodrug thereof.
- a method of modulating the ⁇ -catenin pathway e.g., by inhibiting the expression of beta-catenin target genes
- a method of modulating the ⁇ -catenin pathway e.g., by inhibiting the expression of beta-catenin target genes
- the method is an in vitro method.
- the method is an in vivo method.
- a method of treating a JAK-STAT pathway-associated condition included administering to a subject in need thereof a compound of the present invention or a pharmaceutically acceptable composition, salt, isotopic analog (such as a deuterated derivative), or prodrug thereof.
- a method of modulating the STAT1 activity in a cell e.g., by inhibiting phosphorylation of STAT1 S727 in the JAK-STAT pathway, leading to up- or down-regulation of specific STAT 1 -associated genes
- the method is an in vitro method.
- the method is an in vivo method.
- a method of treating a TGF-beta/BMP pathway- associated condition comprising administering to a subject in need thereof a compound of the present invention or a pharmaceutically acceptable composition, salt, isotopic analog (such as a deuterated derivative) or prodrug thereof.
- a method of modulating the TGF-beta/BMP pathway e.g., by inhibiting CDK8/CDK19 phosphorylation SMAD proteins in the TGF-beta/BMP pathway leading to up- or down-regulation of specific SMAD protein- associated genes
- a cell comprising contacting a compound of the present invention or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof, with the cell.
- the method is an in vitro method.
- the method is an in vivo method.
- CDK8 has been linked to regulation of hypoxic response, playing a role in induction of HIF-l-A (HIF-l-alpha) target genes. These genes are involved in angiogenesis, glycolysis, metabolic adaption, and cell survival, processes critical to tumor maintenance and growth. See, e.g., Galbraith, et al., Cell 153 : 1327-1339.
- a method of treating a condition associated with hypoxia comprising administering to a subject in need thereof a compound of the present invention or a pharmaceutically acceptable composition, salt, isotopic analog (such as a deuterated derivative), or prodrug thereof.
- a method of reducing hypoxia injury comprising administering to a subject in need thereof a compound of the present invention or a pharmaceutically acceptable composition, salt, isotopic analog (such as a deuterated derivative), or prodrug thereof.
- a method of modulating HIF-l-A (HIF-1 -alpha) activity e.g., by inhibiting the expression HIF-1- alpha associated genes
- the method is an in vitro method.
- the method is an in vivo method.
- BCL2L11 is downregulated in many cancers and BIM is inhibited in many cancers, including chronic myelocytic leukemia (CML) and non-small cell lung cancer (NSCLC) and that suppression of BCL2L11 expression can confer resistance to tyrosine kinase inhibitors.
- CML chronic myelocytic leukemia
- NSCLC non-small cell lung cancer
- a method of treating a condition associated with angiogenesis comprising administering to a subject in need thereof a compound of the present invention or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof.
- a diabetic condition e.g., diabetic retinopathy
- an inflammatory condition e.g., rheumatoid arthritis
- macular degeneration e.g., obesity, atherosclerosis, or a proliferative disorder
- a "diabetic condition” refers to diabetes and pre-diabetes. Diabetes refers to a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced. This high blood sugar produces the classical symptoms of polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger). There are several types of diabetes. Type I diabetes results from the body's failure to produce insulin, and presently requires the person to inject insulin or wear an insulin pump. Type 2 diabetes results from insulin resistance a condition in which cells fail to use insulin properly, sometimes combined with an absolute insulin deficiency.
- Gestational diabetes occurs when pregnant women without a previous diagnosis of diabetes develop a high blood glucose level.
- Other forms of diabetes include congenital diabetes, which is due to genetic defects of insulin secretion, cystic fibrosis-related diabetes, steroid diabetes induced by high doses of glucocorticoids, and several forms of monogenic diabetes, e.g., mature onset diabetes of the young (e.g., MODY 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10).
- Pre-diabetes indicates a condition that occurs when a person's blood glucose levels are higher than normal but not high enough for a diagnosis of diabetes.
- diabetes all forms of diabetes increase the risk of long-term complications (referred to herein as the "associated complication" of the diabetic condition). These typically develop after many years, but may be the first symptom in those who have otherwise not received a diagnosis before that time.
- a major long-term complication relates to damage to blood vessels. Diabetes doubles the risk of cardiovascular disease and macrovascular diseases such as ischemic heart disease (angina, myocardial infarction), stroke, and peripheral vascular disease. Diabetes also causes microvascular complications, e.g., damage to the small blood vessels. Diabetic retinopathy, which affects blood vessel formation in the retina of the eye, can lead to visual symptoms, reduced vision, and potentially blindness.
- Diabetic nephropathy the impact of diabetes on the kidneys, can lead to scarring changes in the kidney tissue, loss of small or progressively larger amounts of protein in the urine, and eventually chronic kidney disease requiring dialysis.
- Diabetic neuropathy is the impact of diabetes on the nervous system, most commonly causing numbness, tingling and pain in the feet and also increasing the risk of skin damage due to altered sensation. Together with vascular disease in the legs, neuropathy contributes to the risk of diabetes-related foot problems, e.g., diabetic foot ulcers that can be difficult to treat and occasionally require amputation.
- the associated complication is diabetic retinopathy.
- a method of treating diabetic retinopathy comprising administering to a subject in need thereof a compound of the present invention or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof.
- the condition associated with angiogenesis is macular degeneration.
- a method of treating macular degeneration comprising administering to a subject in need thereof a compound of the present invention or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof.
- the condition associated with angiogenesis is obesity.
- “obesity” and “obese” as used herein refers to class I obesity, class II obesity, class III obesity and pre-obesity (e.g., being "over-weight") as defined by the World Health Organization.
- a method of treating obesity comprising administering to a subject in need thereof a compound of the present invention or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof.
- the condition associated with angiogenesis is atherosclerosis.
- a method of treating atherosclerosis comprising administering to a subject in need thereof a compound of the present invention or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof.
- the condition associated with angiogenesis is a proliferative disorder.
- a method of treating a proliferative disorder comprising administering to a subject in need thereof a compound of the present invention or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof.
- HCC hepatocellular cancer
- lung cancer e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung
- myelofibrosis MF
- chronic idiopathic myelofibrosis chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)
- neuroblastoma e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis
- neuroendocrine cancer e.g., gastroenteropancreatic neuroendoctrine tumor (GEP- ET), carcinoid tumor
- osteosarcoma ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors), penile cancer (e.g., Paget' s disease of the
- the cancer or tumor is associated with CDK8 and/or CDK19 kinase activity. In certain embodiments, the cancer or tumor is associated with CDK8 kinase activity. In certain embodiments, the cancer or tumor is associated with CDK19 kinase activity. In certain embodiments, the cancer or tumor is associated with aberrant CDK8 kinase activity. In certain embodiments, the cancer or tumor is associated with aberrant CDK19 kinase activity. In certain embodiments, the cancer or tumor is associated with increased CDK8 kinase activity. In certain embodiments, the cancer is associated with increased CDK19 kinase activity.
- the cancer is a hematopoietic cancer.
- the hematopoietic cancer is a lymphoma.
- the hematopoietic cancer is a leukemia.
- the leukemia is acute myelocytic leukemia (AML).
- the proliferative disorder is a myeloproliferative neoplasm.
- the myeloproliferative neoplasm MPN
- PMF primary myelofibrosis
- the disorder is myelodysplastic syndrome (MDS).
- MDS myelodysplastic syndrome
- the cancer is a solid tumor.
- a solid tumor refers to an abnormal mass of tissue that usually does not contain cysts or liquid areas. Different types of solid tumors are named for the type of cells that form them. Examples of classes of solid tumors include, but are not limited to, sarcomas, carcinomas, and lymphomas, as described above herein. Additional examples of solid tumors include, but are not limited to, squamous cell carcinoma, colon cancer, breast cancer, prostate cancer, lung cancer, liver cancer, pancreatic cancer, and melanoma.
- compositions comprising a compound as described herein may be formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions comprising a compound as described herein will be decided by the attending physician within the scope of sound medical judgment.
- the compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol.
- enteral e.g., oral
- parenteral intravenous, intramuscular, intra-arterial, intramedullary
- intrathecal subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal
- topical as by powders, ointments, creams, and/or drops
- mucosal nasal,
- the exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound(s), mode of administration, and the like.
- the desired dosage can be delivered using any frequency determined to be useful by the health care provider, including three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks.
- the desired dosage can be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).
- an effective amount of a compound for administration one or more times a day may comprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 0.1 mg to about 10 mg, or about 0.1 mg to about 15 mg, of a compound per unit dosage form.
- an effective amount of an active agent for administration comprises at least about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg.
- the compound may be administered orally or parenterally to an adult human at dosage levels sufficient to deliver from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and from about 0.01 mg/kg to about 1 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
- dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult.
- the amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.
- a compound or composition, as described herein can be administered in combination with one or more additional therapeutically active agents.
- the compounds or compositions can be administered in combination with additional therapeutically active agents that improve their bioavailability, reduce and/or modify their metabolism, inhibit their excretion, and/or modify their distribution within the body.
- the therapy employed may achieve a desired effect for the same disorder (for example, a compound can be administered in combination with an anti-inflammatory agent, anti-cancer agent, etc.), and/or it may achieve different effects (e.g., control of adverse side-effects, e.g., emesis controlled by an anti-emetic).
- the compound or composition can be administered concurrently with, prior to, or subsequent to, one or more additional therapeutically active agents.
- each agent will be administered at a dose and/or on a time schedule determined for that agent.
- the additional therapeutically active agent utilized in this combination can be administered together in a single composition or administered separately in different compositions.
- the particular combination to employ in a regimen will take into account compatibility of the inventive compound with the additional therapeutically active agent and/or the desired therapeutic effect to be achieved.
- additional therapeutically active agents utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.
- a treatment regimen comprising the administration of a compound of the present invention or a pharmaceutically acceptable composition, salt, isotopic analog (such as a deuterated derivative), or prodrug thereof in combination or in alternation with at least one additional therapeutic agent.
- a compound of the present invention or a pharmaceutically acceptable composition, salt, isotopic analog (such as a deuterated derivative), or prodrug thereof in combination or in alternation with at least one additional therapeutic agent.
- the combinations and/or alternations disclosed herein can be administered for beneficial, additive, or synergistic effect in the treatment of abnormal cellular proliferative disorders.
- the second active compound is an immune modulator, including but not limited to a checkpoint inhibitor.
- Checkpoint inhibitors for use in the methods described herein include, but are not limited to PD-1 inhibitors, PD-L1 inhibitors, PD-L2 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, and V-domain Ig suppressor of T-cell activation (VISTA) inhibitors, or combination thereof.
- the checkpoint inhibitor is a PD-1 inhibitor that blocks the interaction of PD-1 and PD-L1 by binding to the PD-1 receptor, and in turn inhibits immune suppression.
- the checkpoint inhibitor is a PD-1 checkpoint inhibitor selected from nivolumab, pembrolizumab, pidilizumab, AMP-224 (AstraZeneca and Medlmmune), PF-06801591 (Pfizer),
- MEDI0680 (AstraZeneca), PDR001 (Novartis), REGN2810 (Regeneron), SHR-12-1 (Jiangsu).
- TSR-042 Tesaro
- PD-L1/VISTA inhibitor CA-170 Curis Inc.
- the checkpoint inhibitor is a PD-L1 inhibitor that blocks the interaction of PD-1 and PD-L1 by binding to the PD-L1 receptor, and in turn inhibits immune suppression.
- PD-L1 inhibitors include, but are not limited to, avelumab, atezolizumab, durvalumab, KN035, and BMS-936559 (Bristol-Myers Squibb).
- the checkpoint inhibitor is a CTLA-4 checkpoint inhibitor that binds to CTLA-4 and inhibits immune suppression.
- CTLA-4 inhibitors include, but are not limited to, ipilimumab, tremelimumab (AstraZeneca and Medlmmune), AGEN1884 and
- the checkpoint inhibitor is a LAG-3 checkpoint inhibitor.
- LAG-3 checkpoint inhibitors include, but are not limited to, BMS-986016 (Bristol- Myers Squibb), GSK2831781 (GlaxoSmithKline), IMP321 (Prima BioMed), LAG525 (Novartis), and the dual PD-1 and LAG-3 inhibitor MGD013 (MacroGenics).
- the checkpoint inhibitor is a TIM-3 checkpoint inhibitor.
- a specific TIM-3 inhibitor includes, but is not limited to, TSR-022 (Tesaro).
- the compound for use in combination therapy is a LAG-3 targeting ligand. In another embodiment, the compound for use in combination therapy is a TIM- 3 targeting ligand. In another embodiment, the compound for use in combination therapy is a aromatase inhibitor. In another embodiment, the compound for use in combination therapy is a progestin receptor targeting ligand. In another embodiment, the compound for use in
- combination therapy is a CYP3 A4 targeting ligand.
- the compound for use in combination therapy is a TORC1 or TORC2 targeting ligand.
- the treatment regimen includes the administration of a compound of the present invention or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof in combination or alternation with at least one additional kinase inhibitor.
- the at least one additional kinase inhibitor is selected from a phosphoinositide 3- kinase (PI3K) inhibitor, a Bruton's tyrosine kinase (BTK) inhibitor, another cyclin-dependent kinase inhibitor, or a spleen tyrosine kinase (Syk) inhibitor, or a combination thereof.
- the additional active agent is the small molecule BET inhibitor, MK- 8628 (CAS 202590-98-5) (6H-thieno(3,2-f)-(l,2,4)triazolo(4,3-a)-(l,4)diazepine-6-acetamide, 4- (4-chlorophenyl)-N-(4-hydroxyphenyl)2,3,9-trimethyl, (6S).
- a compound of the present invention or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof is combined in a dosage form with the PIk3 inhibitor.
- PI3k inhibitors that may be used in the present invention are well known.
- PI3 kinase inhibitors include but are not limited to Wortmannin, demethoxyviridin, perifosine, idelalisib, Pictilisib, Palomid 529, ZSTK474, PWT33597, CUDC-907, and AEZS-136, duvelisib, GS-9820, GDC-0032 (2-[4-[2-(2-Isopropyl-5-methyl-l,2,4-triazol-3-yl)-5,6-dihydroimidazo[l,2- d][l,4]benzoxazepin-9-yl]pyrazol-l-yl]-2-methylpropanamide), MLN-1117 ((2R)-l-Phenoxy-2- butanyl hydrogen (S)-methylphosphonate; or Methyl(oxo) ⁇ [(2R)-l-phenoxy-2-
- LY3023414, BEZ235 (2-Methy 1-2 - ⁇ 4- [3 -methyl-2-oxo-8-(quinolin-3 -yl)-2, 3 -dihy dro-lH- imidazo[4,5-c]quinolin-l-yl]phenyl ⁇ propanenitrile), XL-765 (N-(3-(N-(3-(3,5- dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide), and GSK1059615 (5-[[4-(4-Pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidenedione), PX886 ([(3aR,6E,9S,9aR,10R,l laS)-6-[[bis(prop-2-enyl)amino]methylidene]-5-hydroxy-9- (methoxymethyl
- BTK inhibitors for use in the present invention are well known.
- BTK inhibitors include ibrutinib (also known as PCI-32765)(ImbruvicaTM)(l-[(3R)-3-[4-amino-3-(4- phenoxy-phenyl)pyrazolo[3 ,4-d]pyrimidin- 1 -yljpiperidin- 1 -yl]prop-2-en- 1 -one),
- dianilinopyrimidine-based inhibitors such as AVL-101 and AVL-291/292 (N-(3-((5-fluoro-2-((4- (2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide) (Avila Therapeutics) (see US Patent Publication No 2011/0117073, incorporated herein in its entirety), Dasatinib ([N- (2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-l-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide], LFM-A13 (alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5- ibromophenyl) propenamide), GDC-0834 ([R-N-(3-(6-(4-(l,4-dimethyl-3-ox
- the additional cyclin-dependent kinase inhibitor is a CDK7 inhibitor such as THZ1 (N-[3-[[5-chloro-4-(lH-indol-3-yl)pyrimidin-2-yl]amino]phenyl]-4-[[(E)-4- (dimethylamino)but-2-enoyl]amino]benzamide).
- the additional cyclin-dependent kinase inhibitor is a CDK9 inhibitor such as flavopiridol (alvocidib).
- a method of treating a tumor or cancer comprising administration of an effective amount of an analog of Compound A or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with an effective amount of a Syk inhibitor to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of an analog of Compound B as provided herein in combination or alternation with an effective amount of a Syk inhibitor to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of an analog of Compound C or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with an effective amount of a Syk inhibitor to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of an analog of Compound D or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with an effective amount of a Syk inhibitor to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of Compound B or a pharmaceutically acceptable salt thereof in combination or alternation with imatinib (Gleevec) to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of Compound C or a pharmaceutically acceptable salt thereof in combination or alternation with imatinib (Gleevec) to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of Compound D or a pharmaceutically acceptable salt thereof in combination or alternation with imatinib (Gleevec) to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of an analog of Compound A or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with imatinib (Gleevec) to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of an analog of Compound B or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with imatinib (Gleevec) to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of an analog of Compound C or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with imatinib (Gleevec) to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of an analog of Compound D or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with imatinib (Gleevec) to a host in need thereof.
- Syk inhibitors for use in the present invention are well known, and include, for example,
- Cerdulatinib (4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-l- yl)phenyl)amino)pyrimidine-5-carboxamide), entospletinib (6-(lH-indazol-6-yl)-N-(4- morpholinophenyl)imidazo[l,2-a]pyrazin-8-amine), fostamatinib ([6-( ⁇ 5-Fluoro-2-[(3,4,5- trimethoxyphenyl)amino]-4-pyrimidinyl ⁇ amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H- pyrido[3,2-b][l,4]oxazin-4-yl]methyl dihydrogen phosphate), fostamatinib disodium salt (sodium (6-((5-fluoro-2-((3,4,5-trime
- a compound of the present invention or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof is combined in a dosage form with the Syk inhibitor.
- the method of treatment provided includes the administration of a compound of the present invention or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof in combination or alternation with at least one additional chemotherapeutic agent.
- the at least one additional chemotherapeutic agent combined or alternated with a compound of the present invention is a protein cell death-1 (PD-1) inhibitor.
- PD- 1 inhibitors are known in the art, and include, for example, nivolumab (BMS), pembrolizumab (Merck), pidilizumab (CureTech/Teva), AMP-244 (Amplimmune/GSK), BMS-936559 (BMS), and MEDI4736 (Roche/Genentech).
- a compound of the present invention or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof is combined in a dosage form with the PD-1 inhibitor.
- the PD-1 inhibitor is pembrolizumab.
- a method of treating a tumor or cancer comprising administration of an effective amount of Compound B or a pharmaceutically acceptable salt thereof in combination or alternation with an effective amount of a PD-1 inhibitor to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of Compound C or a pharmaceutically acceptable salt thereof in combination or alternation with an effective amount of a PD-1 inhibitor to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of Compound D or a pharmaceutically acceptable salt thereof in combination or alternation with an effective amount of a PD-1 inhibitor to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of an analog of Compound A or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with an effective amount of a PD-1 inhibitor to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of an analog of Compound B or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with an effective amount of a PD-1 inhibitor to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of an analog of Compound C or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with an effective amount of a PD-1 inhibitor to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of an analog of Compound D or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with an effective amount of a PD-1 inhibitor to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of Compound B or a pharmaceutically acceptable salt thereof in combination or alternation with pembrolizumab (Keytruda).
- a method of treating a tumor or cancer comprising administration of an effective amount of Compound C or a pharmaceutically acceptable salt thereof in combination or alternation with pembrolizumab (Keytruda).
- a method of treating a tumor or cancer comprising administration of an effective amount of Compound D or a pharmaceutically acceptable salt thereof in combination or alternation with pembrolizumab (Keytruda).
- a method of treating a tumor or cancer comprising administration of an effective amount of an analog of Compound A or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with pembrolizumab (Keytruda).
- a method of treating a tumor or cancer comprising administration of an effective amount of an analog of Compound B or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with pembrolizumab (Keytruda).
- a method of treating a tumor or cancer comprising administration of an effective amount of an analog of Compound C or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with pembrolizumab (Keytruda).
- a method of treating a tumor or cancer comprising administration of an effective amount of an analog of Compound D or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with pembrolizumab (Keytruda).
- the at least one additional chemotherapeutic agent combined or alternated with a compound of the present invention is a CTLA-4 inhibitor.
- CTLA-4 inhibitors are known in the art, and include, for example, ipilimumab (Yervoy) marketed by Bristol-Myers Squibb and tremelimumab marketed by Pfizer.
- the at least one additional chemotherapeutic agent combined or alternated with the compound of the present invention is a BET inhibitor.
- BET inhibitors are known in the art, and include, for example, JQ1, I-BET 151 (a.k.a. GSK1210151A), I-BET 762 (a.k.a. GSK525762), OTX-015 (a.k.a.
- the BET inhibitor used in combination or alternation with a compound of the present invention for treatment of a tumor or cancer is JQ1 ((S)-tert-butyl 2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- f][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)acetate).
- the BET inhibitor used in combination or alternation with a compound of the present invention for treatment of a tumor or cancer is I-BET 151 (2H-Imidazo[4,5-c]quinolin-2-one, 7-(3,5-dimethyl-4-isoxazolyl)- l,3-dihydro-8-methoxy-l-[(lR)-l-(2-pyridinyl)ethyl]-).
- a method of treating a tumor or cancer comprising administration of an effective amount of Compound B or a pharmaceutically acceptable salt thereof in combination or alternation with an effective amount of a BET inhibitor to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of Compound C or a pharmaceutically acceptable salt thereof in combination or alternation with an effective amount of a BET inhibitor to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of Compound D or a pharmaceutically acceptable salt thereof in combination or alternation with an effective amount of a BET inhibitor to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of an analog of Compound A or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with an effective amount of a BET inhibitor to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of an analog of Compound B or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with an effective amount of a BET inhibitor to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of an analog of Compound C or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with an effective amount of a BET inhibitor to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of an analog of Compound D or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with an effective amount of a BET inhibitor to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of Compound B or a pharmaceutically acceptable salt thereof in combination or alternation with JQ1.
- a method of treating a tumor or cancer comprising administration of an effective amount of Compound C or a pharmaceutically acceptable salt thereof in combination or alternation with JQ1.
- a method of treating a tumor or cancer comprising administration of an effective amount of Compound D or a pharmaceutically acceptable salt thereof in combination or alternation with JQ1.
- a method of treating a tumor or cancer comprising administration of an effective amount of an analog of Compound A or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with JQ1.
- a method of treating a tumor or cancer comprising administration of an effective amount of an analog of Compound B or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with JQ1.
- a method of treating a tumor or cancer comprising administration of an effective amount of an analog of Compound C or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with JQ 1.
- a method of treating a tumor or cancer comprising administration of an effective amount of an analog of Compound D or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with JQ1.
- a method of treating a tumor or cancer comprising administration of an effective amount of Compound B or a pharmaceutically acceptable salt thereof in combination or alternation with I-BET 151.
- a method of treating a tumor or cancer comprising administration of an effective amount of Compound C or a pharmaceutically acceptable salt thereof in combination or alternation with I-BET 151.
- a method of treating a tumor or cancer comprising administration of an effective amount of Compound D or a pharmaceutically acceptable salt thereof in combination or alternation with I-BET 151.
- a method of treating a tumor or cancer comprising administration of an effective amount of an analog of Compound A or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with I- BET 151.
- a method of treating a tumor or cancer comprising administration of an effective amount of an analog of Compound B or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with I-BET 151.
- a method of treating a tumor or cancer comprising administration of an effective amount of an analog of Compound C or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with I-BET 151.
- a method of treating a tumor or cancer is provided, comprising administration of an effective amount of an analog of Compound D or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with I-BET 151.
- the at least one additional chemotherapeutic agent combined or alternated with the compound of the present invention is a MEK inhibitor.
- MEK inhibitors for use in the present invention are well known, and include, for example, tametinib/GSKl 120212 (N-(3- ⁇ 3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin-l(2H-yl ⁇ phenyl)acetamide), selumetinob (6-(4-bromo-2- chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), pimasertib/AS703026/MSC 1935369 ((S)-N-(2,3-dihydroxypropyl)-3-((2-
- the at least one additional chemotherapeutic agent combined or alternated with the compound of the present invention is a Raf inhibitor.
- Raf inhibitors for use in the present invention are well known, and include, for example, Vemurafinib (N-[3-[[5-(4- Chlorophenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl]-l- propanesulfonamide), sorafenib tosylate (4-[4-[[4-chloro-3-
- the at least one additional chemotherapeutic agent combined or alternated with the compound of the present invention is a B-cell lymphoma 2 (Bcl-2) protein inhibitor.
- BCL-2 inhibitors are known in the art, and include, for example, ABT-199 (4-[4-[[2-(4- Chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl]piperazin-l-yl]-N-[[3-nitro-4- [[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(lH- pyrrolo[2,3-b]pyridin-5- yl)oxy]benzamide), ABT-737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-l-yl]-N-[4- [[(2R)-4-(dimethylamino)-l-
- a compound of the present invention or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof is combined in a dosage form with the at least one BCL-2 inhibitor.
- the at least one BCL-2 inhibitor is ABT-199 (Venetoclax).
- a method of treating a tumor or cancer comprising administration of an effective amount of Compound B or a pharmaceutically acceptable salt thereof in combination or alternation with an effective amount of a BCL-2 inhibitor to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of Compound C or a pharmaceutically acceptable salt thereof in combination or alternation with an effective amount of a BCL-2 inhibitor to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of Compound D or a pharmaceutically acceptable salt thereof in combination or alternation with an effective amount of a BCL-2 inhibitor to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of an analog of Compound A or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with an effective amount of a BCL-2 inhibitor to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of an analog of Compound B or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with an effective amount of a BCL-2 inhibitor to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of an analog of Compound C or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with an effective amount of a BCL-2 inhibitor to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of an analog of Compound D or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with an effective amount of a BCL-2 inhibitor to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of Compound B or a pharmaceutically acceptable salt thereof in combination or alternation with ABT-199 to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of Compound C or a pharmaceutically acceptable salt thereof in combination or alternation with ABT-199 to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of Compound D or a pharmaceutically acceptable salt thereof in combination or alternation with ABT-199 to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of an analog of Compound A or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with ABT-199 to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of an analog of Compound B or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with ABT-199 to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of an analog of Compound C or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with ABT-199 to a host in need thereof.
- a method of treating a tumor or cancer comprising administration of an effective amount of an analog of Compound D or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with ABT-199 to a host in need thereof.
- the treatment regimen includes the administration of a compound of the present invention or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof in combination or alternation with at least one additional chemotherapeutic agent selected from, but are not limited to, Imatinib mesylate (Gleevac), Dasatinib (Sprycel), Nilotinib (Tasigna), Bosutinib (Bosulif), Trastuzumab (Herceptin), Pertuzumab (PerjetaTM), Lapatinib (Tykerb), Gefitinib (Iressa), Erlotinib (Tarceva), Cetuximab (Erbitux), Panitumumab (Vectibix), Vandetanib (Caprelsa), Vemurafenib (Zelboraf), Vorinostat (Zolinza), Romidepsin (Istodax), Bexarotene (Tagretin), Alitret
- the pharmaceutical combination or composition described herein can be administered to the subject in combination or further combination with other chemotherapeutic agents for the treatment of a tumor or cancer. If convenient, the pharmaceutical combination or composition described herein can be administered at the same time as another chemotherapeutic agent, in order to simplify the treatment regimen. In some embodiments, the pharmaceutical combination or composition and the other chemotherapeutic can be provided in a single formulation. In one embodiment, the use of the pharmaceutical combination or composition described herein is combined in a therapeutic regime with other agents.
- Such agents may include, but are not limited to, tamoxifen, midazolam, letrozole, bortezomib, anastrozole, goserelin, an mTOR inhibitor, a PI3 kinase inhibitor as described above, a dual mTOR-PI3K inhibitor, a MEK inhibitor as described above, a RAS inhibitor, ALK inhibitor, an HSP inhibitor (for example, HSP70 and HSP 90 inhibitor, or a combination thereof), a BCL-2 inhibitor as described above, apopototic inducing compounds, an AKT inhibitor, including but not limited to, MK-2206 (1,2,4- Triazolo[3,4-f][l,6]naphthyridin-3(2H)-one, 8-[4-(l-aminocyclobutyl)phenyl]-9-phenyl-), GSK690693, Perifosine, (KRX-0401), GDC-0068, Triciribine, AZD
- mTOR inhibitors include but are not limited to rapamycin and its analogs, everolimus (Afinitor), temsirolimus, ridaforolimus, sirolimus, and deforolimus.
- RAS inhibitors include but are not limited to Reolysin and siG12D LODER.
- ALK inhibitors include but are not limited to Crizotinib, AP26113, and LDK378.
- HSP inhibitors include but are not limited to Geldanamycin or 17-N-Allylamino-17-demethoxygeldanamycin (17AAG), and Radicicol.
- a compound described herein is administered in combination with letrozole and/or tamoxifen.
- Other chemotherapeutic agents that can be used in combination with the compounds described herein include, but are not limited to, chemotherapeutic agents that do not require cell cycle activity for their anti -neoplastic effect.
- the treatment regimen includes the administration of a compound of the present invention or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof in combination or alternation with at least one additional therapy.
- the second therapy can be an immunotherapy.
- the combination agent can be conjugated to an antibody, radioactive agent, or other targeting agent that directs the active compound as described herein to the diseased or abnormally proliferating cell.
- the pharmaceutical combination or composition is used in combination with another pharmaceutical or a biologic agent (for example an antibody) to increase the efficacy of treatment with a combined or a synergistic approach.
- the pharmaceutical combination or composition can be used with T-cell vaccination, which typically involves immunization with inactivated autoreactive T cells to eliminate a cancer cell population as described herein.
- the pharmaceutical combination or composition is used in combination with a bispecific T-cell Engager (BiTE), which is an antibody designed to simultaneously bind to specific antigens on endogenous T cells and cancer cells as described herein, linking the two types of cells.
- BiTE bispecific T-cell Engager
- the additional therapy is a monoclonal antibody (MAb).
- MAbs stimulate an immune response that destroys cancer cells. Similar to the antibodies produced naturally by B cells, these MAbs "coat" the cancer cell surface, triggering its destruction by the immune system.
- bevacizumab targets vascular endothelial growth factor(VEGF), a protein secreted by tumor cells and other cells in the tumor' s microenvironment that promotes the development of tumor blood vessels. When bound to bevacizumab, VEGF cannot interact with its cellular receptor, preventing the signaling that leads to the growth of new blood vessels.
- VEGF vascular endothelial growth factor
- cetuximab and panitumumab target the epidermal growth factor receptor (EGFR), and trastuzumab targets the human epidermal growth factor receptor 2 (HER-2).
- MAbs that bind to cell surface growth factor receptors prevent the targeted receptors from sending their normal growth-promoting signals. They may also trigger apoptosis and activate the immune system to destroy tumor cells.
- Immunotherapies with T cells engineered to recognize cancer cells via bispecific antibodies (bsAbs) or chimeric antigen receptors (C ARs) are approaches with potential to ablate both dividing and non/slow-dividing subpopulations of cancer cells.
- Bispecific antibodies by simultaneously recognizing target antigen and an activating receptor on the surface of an immune effector cell, offer an opportunity to redirect immune effector cells to kill cancer cells.
- Another approach is the generation of chimeric antigen receptors by fusing extracellular antibodies to intracellular signaling domains. Chimeric antigen receptor-engineered T cells are able to specifically kill tumor cells in a MHC-independent way.
- the additional therapy is another therapeutic agent, for example, an antiinflammatory agent, a chemotherapeutic agent, a radiotherapeutic agent, or an immunosuppressive agent.
- Suitable chemotherapeutic agents include, but are not limited to, a radioactive molecule, a toxin, also referred to as cytotoxin or cytotoxic agent, which includes any agent that is detrimental to the viability of cells, and liposomes or other vesicles containing chemotherapeutic compounds.
- General anticancer pharmaceutical agents include: Vincristine (Oncovin) or liposomal vincristine (Marqibo), Daunorubicin (daunomycin or Cerubidine) or doxorubicin (Adriamycin), Cytarabine (cytosine arabinoside, ara-C, or Cytosar), L-asparaginase (Elspar) or PEG-L-asparaginase (pegaspargase or Oncaspar), Etoposide (VP- 16), Teniposide (Vumon), 6-mercaptopurine (6-MP or Purinethol), Methotrexate, Cyclophosphamide (Cytoxan), Prednisone, Dexamethasone (Decadron), imatinib (Gleevec marketed by Novartis), dasatinib (Sprycel), nilotinib (Tasigna), bosutinib (Bosulif), and ponat
- chemotherapeutic agents include but are not limited to 1-dehydrotestosterone, 5-fluorouracil decarbazine, 6- mercaptopurine, 6-thioguanine, actinomycin D, adriamycin, aldesleukin, an alkylating agent, allopurinol sodium, altretamine, amifostine, anastrozole, anthramycin (AMC)), an anti-mitotic agent, cis-dichlorodiamine platinum (II) (DDP) cisplatin), diamino dichloro platinum, anthracycline, an antibiotic, an antimetabolite, asparaginase, BCG live (intravesical), betamethasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, calcium leucouorin, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine (BS
- Suitable immunosuppressive agents include, but are not limited to: calcineurin inhibitors, e.g. a cyclosporin or an ascomycin, e.g. Cyclosporin A (NEORAL), FK506 (tacrolimus), pimecrolimus, a mTOR inhibitor, e.g. rapamycin or a derivative thereof, e.g. Sirolimus (RAPAMU E), Everolimus (Certican), temsirolimus, zotarolimus, biolimus-7, biolimus-9, a rapalog, e.g.ridaforolimus, azathioprine, campath 1H, a SIP receptor modulator, e.g.
- fingolimod or an analog thereof an anti IL-8 antibody, mycophenolic acid or a salt thereof, e.g. sodium salt, or a prodrug thereof, e.g. Mycophenolate Mofetil (CELLCEPT), OKT3 (ORTHOCLO E OKT3), Prednisone, ATGAM, THYMOGLOBULIN, Brequinar Sodium, OKT4, T10B9.A-3A, 33B3.1, 15-deoxyspergualin, tresperimus, Leflunomide ARAVA, CTLAI-Ig, anti-CD25, anti-IL2R, Basiliximab (SIMULECT), Daclizumab (ZENAPAX), mizorbine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus, Elidel), CTLA41g (Abatacept), belatacept, LFA31g contend etanercept (sold as Enbrel by Immun
- a pharmaceutical combination or composition described herein is administered to the subject prior to treatment with another chemotherapeutic agent, during treatment with another chemotherapeutic agent, after administration of another chemotherapeutic agent, or a combination thereof.
- the selective pharmaceutical combination or composition can be administered to the subject such that the other chemotherapeutic agent can be administered either at higher doses (increased chemotherapeutic dose intensity) or more frequently (increased chemotherapeutic dose density).
- Dose-dense chemotherapy is a chemotherapy treatment plan in which drugs are given with less time between treatments than in a standard chemotherapy treatment plan.
- Chemotherapy dose intensity represents unit dose of chemotherapy administered per unit time. Dose intensity can be increased or decreased through altering dose administered, time interval of administration, or both.
- the pharmaceutical combination or composition described herein can be administered in a concerted regimen with another agent such as a non- DNA-damaging, targeted anti -neoplastic agent or a hematopoietic growth factor agent.
- another agent such as a non- DNA-damaging, targeted anti -neoplastic agent or a hematopoietic growth factor agent.
- hematopoietic growth factors can have serious side effects.
- the use of the EPO family of growth factors has been associated with arterial hypertension, cerebral convulsions, hypertensive encephalopathy, thromboembolism, iron deficiency, influenza like syndromes and venous thrombosis.
- the G-CSF family of growth factors has been associated with spleen enlargement and rupture, respiratory distress syndrome, allergic reactions and sickle cell complications.
- hematopoietic growth factors including, but not limited to, granulocyte colony stimulating factor (G-CSF, for example, sold as Neupogen (filgrastin), Neulasta (peg-filgrastin), or lenograstin), granulocyte-macrophage colony stimulating factor (GM-CSF, for example sold as molgramostim and sargramostim (Leukine)), M-CSF (macrophage colony stimulating factor), thrombopoietin (megakaryocyte growth development factor (MGDF), for example sold as Romiplostim and Eltrombopag) interleukin (IL)-12, interleukin-3, interleukin- 11 (adipogenesis inhibiting factor or oprelvekin), SCF (stem cell factor, steel factor, kit-ligand, or KL) and erythropoiet
- G-CSF granulocyte colony stimulating factor
- Neupogen filamentgrastin
- the pharmaceutical combination or composition is administered prior to administration of the hematopoietic growth factor.
- the hematopoietic growth factor administration is timed so that the pharmaceutical combination or composition's effect on HSPCs has dissipated.
- the growth factor is administered at least 20 hours after the administration of a pharmaceutical combination or composition described herein.
- a pharmaceutical combination or composition described herein can be administered to the subject.
- the subject can be given a single dose of a pharmaceutical combination or composition described herein.
- the activity of an active compound for a purpose described herein can be augmented through conjugation to an agent that targets the diseased or abnormally proliferating cell or otherwise enhances activity, delivery, pharmacokinetics or other beneficial property.
- Fv fragments are the smallest fragment made from enzymatic cleavage of IgG and IgM class antibodies. Fv fragments have the antigen-binding site made of the VH and VC regions, but they lack the CHI and CL regions. The VH and VL chains are held together in Fv fragments by non-covalent interactions.
- a selected compound as described herein can be administered in combination with an antibody fragment selected from the group consisting of an ScFv, domain antibody, diabody, triabody, tetrabody, Bis-scFv, minibody, Fab2, or Fab3 antibody fragment.
- the antibody fragment is a ScFv.
- ScFv single chain variable fragments
- the antibody fragment administered in combination with a selected compound described herein is a bivalent diabody. If the linker length is less than three residues, scFv molecules associate into triabodies or tetrabodies. In one embodiment, the antibody fragment is a triabody. In one embodiment, the antibody fragment is a tetrabody.
- Multivalent scFvs possess greater functional binding affinity to their target antigens than their monovalent counterparts by having binding to two more target antigens, which reduces the off-rate of the antibody fragment.
- the antibody fragment is a minibody. Minibodies are scFv-CH3 fusion proteins that assemble into bivalent dimers.
- the antibody fragment is a Bis-scFv fragment. Bis-scFv fragments are bispecific. Miniaturized ScFv fragments can be generated that have two different variable domains, allowing these Bis-scFv molecules to concurrently bind to two different epitopes.
- a selected compound described herein is administered in conjugation or combination with a bispecific dimer (Fab2) or trispecific dimer (Fab3). Genetic methods are also used to create bispecific Fab dimers (Fab2) and trispecific Fab trimers (Fab3). These antibody fragments are able to bind 2 (Fab2) or 3 (Fab3) different antigens at once.
- Fab2 bispecific dimer
- Fab3 trispecific dimer
- a selected active compound described herein can be linked to a radioisotope to increase efficacy, using methods well known in the art.
- Any radioisotope that is useful against cancer cells can be incorporated into the conjugate, for example, but not limited to, 131 1, 123 I, 192 Ir, 32 P , 90 Sr, 198 Au, 226 Ra, 90 Y, 241 Am, 252 Cf, 60 Co, or 137 Cs.
- the linker chemistry can be important to efficacy and tolerability of the drug conjugates.
- the thio-ether linked T-DMl increases the serum stability relative to a disulfide linker version and appears to undergo endosomal degradation, resulting in intra-cellular release of the cytotoxic agent, thereby improving efficacy and tolerability, See, Barginear, M.F. and Budman, D.R., Trastuzumab-DMl : A review of the novel immune-conjugate for HER2-overexpressing breast cancer, The Open Breast Cancer Journal, 1 : 25-30, (2009).
- composition or combination as described herein can be used to treat any disorder described herein.
- a compound of the present invention is dosed in a combination or composition with an effective amount of a nucleoside or nucleoside analog.
- nucleosides include: azacitidine, decitabine, didanosine, vidarabine, BCX4430, cytarabine, emtricitabine, lamivudine, zalcitabine, abacavir, aciclovir, entecavir, stavudine, telbivudine, zidovudine, idoxuridine, trifluridine, apricitabine, elvucitabine, amdoxovir, and racivir.
- a method of treating tumor or cancer in a subject comprising administration of Compound C or a pharmaceutically acceptable salt thereof in combination or alternation with an effective amount of a nucleoside analog to a host in need thereof.
- a method of treating tumor or cancer in a subject comprising administration of Compound D or a pharmaceutically acceptable salt thereof in combination or alternation with an effective amount of a nucleoside analog to a host in need thereof.
- a method of treating tumor or cancer in a subject comprising administration of an analog of Compound B or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with an effective amount of a nucleoside analog to a host in need thereof.
- a method of treating tumor or cancer in a subject comprising administration of an analog of Compound C or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with an effective amount of a nucleoside analog to a host in need thereof.
- a method of treating tumor or cancer in a subject comprising administration of an analog of Compound D or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with an effective amount of a nucleoside analog to a host in need thereof.
- a method of treating tumor or cancer in a subject comprising administration of Compound C or a pharmaceutically acceptable salt thereof in combination or alternation with azacitidine to a host in need thereof.
- a method of treating tumor or cancer in a subject comprising administration of Compound D or a pharmaceutically acceptable salt thereof in combination or alternation with azacitidine to a host in need thereof.
- a method of treating tumor or cancer in a subject comprising administration of an analog of Compound B or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with azacitidine to a host in need thereof.
- a method of treating tumor or cancer in a subject comprising administration of an analog of Compound C or a pharmaceutically acceptable salt thereof as provided herein in combination or alternation with azacitidine to a host in need thereof.
- Known compound 1 undergoes in situ bromination/elimination to afford conjugated trienone la by treating with NBS in DMSO.
- Diol lb is provided from la by applying dihydroxylation conditions (for example, Os0 4 ).
- Basic conditions for example, DBU
- thermodynamic epimerization of C2-OH to give trans diol lc.
- trienone la is epoxidized (for example, tBuOOH/DBU) to form compound Id, and the epoxide ring can be opened from the allylic CI position in aqueous media to afford trans diol le.
- thermodynamic epimerization affords the formation of cis diol If from le.
- C2-beta-OH lg is selectively generated when compound 1 is treated with iodosobenzene in the presence of organocatalyst D-proline.
- L-proline gives C2-alpha-OH lh.
- C4-alpha-OH li is selectively formed by deprotonation with NaHMDS followed by addition of Davis oxaziridine. Base catalyzed (for example, DBU) thermodynamic epimerization on li gives C4-beta-OH lj.
- Scheme 1-2 Conversion of C3 ketone 1a to three different compounds.
- C3 ketone la diverges to three compounds as shown in Scheme 2.
- reduction of ketone la to Compound A as known in the art followed by deprotonation and alkylation of 2- iodoacetamide affords compound laa.
- Ti(0/Pr) 4 assisted reductive amination with 7,7-dimethyl- 6,8-dioxa-2-azaspiro[3.5]nonane and sodium borohydride followed by HCl treatment completes the synthesis of compound lab.
- the same reductive amination condition can be conducted using c75-(3,4-diolacetonide)-pyrrolidine as an amine building block to give compound lac.
- the Grignard reaction was performed with 20.0 g (113 mmol, 1.00 equiv) of 6-methoxy- l-tetralone and the product was carried forward without purification by flash chromatography. See, e.g., Saraber et al, Tetrahedron 2006, 62, 1726-1742.
- the Torgov's diene was converted to 8,9-unsaturated methoxyethyleneketone 6 (15.0 g, 47% over 3 steps) based on the literature known procedure. See, e.g., Sugahara et al, Tetrahedron Lett. 1996, 37, 7403-7406.
- the DDQ oxidation was performed with 22.0 g (81.4 mmol, 1.0 equiv) of estrone and the product was carried forward without purification by flash chromatography. See, e.g., Stephan et al., Steroid. 1995, 60, 809-811.
- ethylene glycol 110 mL, 1.99 mol, 24.4 equiv
- PTSA PTSA
- the ethyleneketal (mixture of the 8,9 and 9, 11 -unsaturated regioisomers) was dissolved in acetone (420 mL) and K2CO3 (22.5 g, 163 mmol, 2.00 equiv) was added.
- Me 2 S0 4 (9.30 mL, 97.6 mmol, 1.20 equiv) was added and the reaction mixture was warmed to reflux. After 18 hours, the reaction was allowed to cool to room temperature and the acetone was evaporated. A 2M NaOH solution was added (300 mL) and the aqueous phase was extracted with ethyl acetate (2 x 300 mL).
- Epoxy alcohol compounds 8 and 8a Epoxy alcohol compounds 8 and 8a
- the oxidation product was dissolved in dichloromethane (300 mL) and the reaction mixture was cooled to -40 °C followed by the slow addition of DBU (3.90 mL, 25.6 mmol, 2.50 equiv). After 15 minutes, saturated H4CI solution (130 mL) was added and the reaction was allowed to warm to room temperature. The organic and aqueous layers were separated and the aqueous phase was extracted with dichloromethane (2 x 200 mL). The combined organic phases were washed with brine (150 mL), dried over Na 2 S0 4 , and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, eluent: 3: 1 ⁇ 1 : 1 hexanes:EtOAc) to afford enone 11 (3.16 g, 80% in three steps).
- Cyclopropane 13 (2.45 g, 6.06 mmol, 1.00 equiv) and 2,6-di-tert-butyl-4-methylpyridine (4.40 g, 21.2 mmol, 3.50 equiv) were azeotropically dried with benzene and dissolved in dichloromethane (120 mL). 4A molecular sieves (3.1 g) were added and the reaction flask was cooled to 0 °C. A solution of triflic anhydride in dichloromethane (1 M, 12.1 mL, 12.1 mmol 2.00 equiv) was added dropwise and the ice bath was removed to warm the reaction flask to room temperature.
- Trifluoroacetylated product 130 mg, 216 mmol, 1.00 equiv was azeotropically dried with benzene and dissolved in benzene (4.3 mL).
- AIBN 106 mg, 647 ⁇ , 3.00 equiv was added and the reaction flask was degassed by the freeze-pump thaw process (3 cycles).
- BmSnH (1.16 mL, 4.31 mmol, 20.0 equiv) was added and the reaction mixture was allowed to warm to reflux. After 3 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure.
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- 2016-12-21 RU RU2018133138A patent/RU2018133138A/en not_active Application Discontinuation
- 2016-12-21 MX MX2018009998A patent/MX2018009998A/en unknown
- 2016-12-21 WO PCT/US2016/068143 patent/WO2017142621A1/en active Application Filing
- 2016-12-21 KR KR1020187026651A patent/KR20180110134A/en unknown
- 2016-12-21 EP EP16890889.5A patent/EP3416970A4/en not_active Withdrawn
- 2016-12-21 CN CN201680084734.XA patent/CN109415382A/en active Pending
- 2016-12-21 CA CA3014581A patent/CA3014581A1/en not_active Abandoned
- 2016-12-21 JP JP2018543351A patent/JP2019509996A/en active Pending
Also Published As
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CA3014581A1 (en) | 2017-08-24 |
CN109415382A (en) | 2019-03-01 |
US20190062340A1 (en) | 2019-02-28 |
JP2019509996A (en) | 2019-04-11 |
WO2017142621A1 (en) | 2017-08-24 |
KR20180110134A (en) | 2018-10-08 |
EP3416970A4 (en) | 2019-07-24 |
RU2018133138A (en) | 2020-03-19 |
MX2018009998A (en) | 2018-12-10 |
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